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Similar fecal SCFA patterns despite diverse gut microbiota in Polish and Japanese children during the first two years of life. The longitudinal, comparative, validated study
No full textBACKGROUND: Early-life gut microbiome assembly is shaped by environment, diet, and perinatal exposures. Whether population context shifts taxonomic trajectories and functional outputs similarly remains unclear. METHODS: We re-analyzed longitudinal infant cohorts from Poland (PL) and Japan (JP) across five time points (1 week, 1 month, 6 months, 1 year, 2 years). Amplicon sequence variants (ASVs) were processed uniformly. Cross-sectional alpha diversity (richness, evenness, Shannon, Simpson) was modeled with covariate adjustment (sex, antibiotics, diet). Beta diversity used Bray-Curtis distances (PCoA) and PERMANOVA (unadjusted/adjusted). Confounder-aware genus-level differential abundance identified features not reducible to covariates. Longitudinal genus trajectories and genus-SCFA (acetate, propionate, butyrate, isobutyrate) associations were tested using mixed-effects models. SCFAs were z-score-normalized to harmonize units across cohorts. Sensitivity analyses restricted PL to vaginally delivered infants. Finnish (FIN) and United States (US) cohorts were included for taxonomic validation. RESULTS: Evenness, Shannon, and Simpson were similar between PL and JP at most time points; richness was higher in PL at 1 week with trends at 6 months. Beta diversity showed a significant country effect at every time point except 1 month, robust to covariate adjustment and to restriction to 74 genera shared between PL and JP. Genus-level differential abundance yielded 33 features (26 enriched in PL, 7 in JP) without consistent cross-time recurrence. Longitudinally, most genus trajectories were cohort-specific; genus-SCFA associations were largely population-specific (few overlaps for butyrate/isobutyrate, none for acetate/propionate). Despite taxonomic and association differences, SCFA trajectories did not differ between cohorts after harmonization and adjustment. FIN/US validation supported the robustness of temporal taxonomic signals with few discordances. CONCLUSIONS: Taxonomic profiles and genus-SCFA relationships diverge across populations, whereas core metabolic outputs (fecal SCFAs) follow a conserved, resilient trajectory in early life. This "divergent taxa, convergent function" pattern suggests early-life interventions should prioritize functional maturation over targeting specific taxa. Broader multi-omic studies integrating growth, immune, and neurodevelopmental outcomes are warranted
Dyadic coping of NMOSD and MOGAD patients and their partners: a sociological and psychological examination of strategies (CoMMOnsense-Study)
Get PDFBACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD) impose psychological burdens on patients. Chronic illnesses create challenges for both patients and their partners, who also play a crucial role in managing disease-related stress. Despite its relevance, little is known about the role of dyadic coping (DC) in these conditions. This study investigates DC in NMOSD and MOGAD, aiming to provide clinical recommendations.
METHODS: The CoMMOnsense-Study is a cross-sectional, prospective study of 59 NMOSD and 50 MOGAD patients and their respective partners, recruited from 15 centres of the German Neuromyelitis Optica Study Group registry. Participants completed self-report questionnaires on DC, depression, anxiety and quality of relationship. Correlation analyses were performed to compare findings based on antibody status. Subsequently, multivariate regression analyses were conducted to identify relevant predictors of DC.
RESULTS: Patients with NMOSD and MOGAD demonstrated higher levels of depressive symptoms (NMOSD: p=0.007; MOGAD: p=0.023) and stress communication scores (NMOSD: p=0.022; MOGAD: p=0.013) than their partners. Negative coping was low across all subgroups (Stanine 1). Despite high DC and relationship quality, discrepancies were observed in the coping perceptions between partners.
CONCLUSIONS: Coping is highly shared within partnerships affected by NMOSD and MOGAD, while discrepancies in coping perceptions and protective buffering suggest the presence of unfavourable coping mechanisms. Reducing protective buffering and illness-related distortions shows potential areas for enhancing DC
Pooled overexpression screening identifies PIPPI as a novel microprotein involved in the ER stress response
Get PDFMicroproteins encoded by short open reading frames (sORFs) of <100 codons have been predicted to constitute a substantial fraction of the eukaryotic proteome. However, the relevance and roles of a majority of microproteins remain undefined, as only a small fraction of these intriguing cellular players have been characterized in-depth so far. Here, we use pooled overexpression screens with a library of 11 338 sORFs to overcome the challenge of elucidating which of the thousands of putative translated sORFs are biologically functional. As a proof-of-concept, we performed a phenotypic screen to identify sORFs protecting cells from treatment with the nucleotide analogue 6-thioguanine. With this approach, we identified two cytoprotective microproteins: altDDIT3 and PIPPI. PIPPI is encoded within the LCR16a core duplicon of the Morpheus/NPIP gene cluster. We show that PIPPI modulates the cellular response to protein folding stress in the endoplasmic reticulum (ER) and interacts with proteins in the same pathway, including protein disulfide isomerase ERp44. PIPPI overexpression protects, while PIPPI knockdown sensitizes cells to ER stress. Besides providing mechanistic insights into a new microprotein, this study highlights the power of using pooled overexpression screens to identify functional microproteins
Serum neurofilament light is associated with future disease activity in clinically isolated syndrome and early multiple sclerosis only after non-optic neuritis onset
Get PDFBACKGROUND: We compared the prognostic value of serum neurofilament light chain (sNFL) and glial fibrillary acidic protein (sGFAP) for clinical and radiologic disease activity among patients with clinically isolated syndrome or early multiple sclerosis (MS) with optic neuritis (pwON) and non-optic neuritis (pwNON) as the first manifestation.
METHODS: Patients within 7 months (pwON and pwNON) from disease onset and patients with MS with a disease duration longer than 12 months (pwMS) as controls were included. sNFL and sGFAP were analyzed at baseline and at follow-ups using SIMOA technology. Linear mixed models and Cox regression analyses were applied.
RESULTS: We included 165 samples of 86 patients (18 pwON, 46 pwNON, 21 pwMS). Median follow-up time was 80 months. Mean sNFL z scores were higher in pwNON (1.06) than pwON (0.53) and pwMS (0.94). In pwNON, but not pwON, higher sNFL z scores were associated with an elevated risk for a subsequent attack (pwNON: HR 1.63 [95% CI 1.12 to 2.27], p = 0.005; pwON: HR 0.80 [95% CI 0.51-2.27], p = 0.318) and new MRI T2 lesions (pwNON: HR 1.66 [95% CI 1.31 to 2.11], p < 0.001; pwON: HR 1.16 [95% CI 0.82 to 1.63], p = 0.404). sGFAP z scores were associated with a lower risk of a subsequent attack in pwON (HR 0.34 [95% CI 0.12 to 0.98], p = 0.047).
CONCLUSION: sNFL but not sGFAP predicted future clinical and MRI disease activity only in pwNON, potentially suggesting that the prognostic value of sNFL may depend on the type of the first manifestation
Key priorities for the implementation of the 2023 ESC Guidelines for the management of cardiomyopathies in low-resource settings
No full textESC Guidelines provide best practice, evidence-based recommendations for diagnosing and treating patients with cardiovascular diseases. It is not always possible for best practices to be followed, however, particularly in low-resource settings. To address this issue, a set of guideline-related documents were created to identify key priorities for users in these settings. The documents highlight the related recommendations and describe key strategies for clinicians to approach implementation of these recommendations or discuss alternatives which are in line with the intention of the recommendations, if not having all of the same advantages. The suggestions cannot be used as exact substitutes for the original recommendations in the guidelines, which have not been altered and continue to reflect best practice. This document on key priorities for low-resource settings was developed by the task force chairs and other members of the task force who produced the 2023 ESC Guidelines for the management of cardiomyopathies, which are freely available on the ESC website (https://www.escardio.org/Guidelines). This document also underwent external review including international experts from within and beyond Europe and ESC partner organizations, including the Interamerican Society of Cardiology, the Pan-African Society of Cardiology, the Asian Pacific Society of Cardiology, and the ASEAN Federation of Cardiology
Immunologic effects of locoregional therapies for unresectable hepatocellular carcinoma
Get PDFBACKGROUND & AIMS: The combination of locoregional therapies (LRT) with immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma (HCC) is expected to enhance immune-mediated anti-tumor effects. Although clinical trials are underway, an unmet need exists to understand the immunological effects of LRT and how they evolve. This study aimed to longitudinally assess immune cell subpopulations and checkpoint expression after LRT. METHODS: This prospective, single-center study (DRKS00026994) enrolled 128 consecutive patients with unresectable HCC, who underwent conventional transarterial chemoembolization (cTACE), interstitial high-dose-rate brachytherapy (iBT), or a combination of cTACE and iBT (from July 2020 to September 2021). Peripheral blood samples were collected at baseline, 1 day after LRT, and 2 months after LRT. Immune cells were quantified using spectral flow cytometry. Immune cell subpopulations and checkpoint molecule expression were compared longitudinally and among treatment groups. Cluster analyses were used to explore immune profiles and their relationship with treatment response. RESULTS: Changes in absolute immune cell counts were detected 1 day after LRT, which largely diminished by 2 months. Myeloid populations increased significantly, whereas most lymphoid cells decreased after LRT. However, relative proportions of antitumoral CD56(diminished) NK cells (Cohen’s D = 0.40, 95% CI 0.19–0.61, p <0.01), CD8(+) T cells (Cohen’s D = 0.15, 95% CI -0.06 to 0.35, p = 0.01), and CTLA-4 expression on T cells (CD4(+): Cohen’s D = 0.54, 95% CI 0.33–0.75, p <0.01; CD8(+): Cohen’s D = 0.15, 95% CI 0.36–0.78, p <0.01) were upregulated at 1 day, particularly after cTACE. Cluster analysis distinguished responders from non-responders based on distinct immune profiles. CONCLUSIONS: LRT induce an early pro-inflammatory immune response with increased myeloid, CTLA-4(+) T cells, and cytotoxic lymphocytes, particularly after cTACE. These findings support the potential of immune profiling to guide personalized combination strategies with LRT and systemic immunotherapies. CLINICAL TRIAL NUMBER: DRKS00026994 (https://drks.de/search/de/trial/DRKS00026994)
Extracellular microRNAs modulate human microglial function through TLR8
Get PDFOBJECTIVE: MicroRNAs (miRNAs) are abundantly expressed in the brain and are specifically dysregulated in central nervous system (CNS) diseases. They act as post-transcriptional gene regulators but can also serve as ligands for Toll-like receptors (TLRs). This study aims to investigate CNS disease-associated miRNAs as signaling molecules for human microglia. METHODS: Using a machine learning algorithm and the disease-linked database PhenoMiR, we identified Alzheimer’s disease (AD)- and glioma-associated miRNAs as ligands for TLR7 and TLR8. Expression of human TLR7 and TLR8 in iPSC-derived human microglia-like cells (iMGLs) was validated by RT-qPCR. Using ELISA, scratch assay, and FACS, we investigated the miRNAs’ potential to modulate iMGL function, including cytokine release, motility, and phagocytosis, respectively. The selective human TLR8 antagonist CU-CPT9a was used to determine the role of this receptor in miRNA-induced modulation of human microglial activity. Co-cultures of iMGLs and iPSC-derived human cortical neurons (iNeurons) were analyzed by Neurotrack imaging to assess the effects of miRNAs on human neurites. RESULTS: We identified AD- and glioma-associated miR-9-5p, miR-132-5p, miR-340-3p, miR-30e-3p, miR-501-3p, and let-7b as ligands for human TLR7 and TLR8. Exposure of iMGLs to select miRNAs, including miR-9-5p, miR-132-5p, and miR-340-3p, led to interleukin-6 (IL-6) and tumor necrosis factor (TNF) mRNA expression and protein release in a sequence-dependent fashion. Also, these miRNAs acting as signaling molecules, modulated iMGL motility and phagocytosis activity. The miRNA-induced effects on iMGLs were abolished by CU-CPT9a. Extracellular delivery of miR-132-5p and miR-9-5p to co-cultures of iNeurons and iMGLs resulted in reduced neurite length. DISCUSSION: Our data establish that distinct CNS disease-associated miRNAs serve as signaling molecules for human microglia via TLR8, thereby controlling the diverse microglial functions and modulating the neuroinflammatory response
StemCNV-check: a pipeline for human pluripotent stem cell (hPSC) genomic integrity control using SNP array data and copy number variant scoring
No full textHuman pluripotent stem cells (hPSCs) and other continuously cultured cell lines are prone to acquiring
mutations and genomic aberrations over time, even when derived from well-characterized cell banks. To
ensure experimental reproducibility and maintain cell line integrity, routine monitoring for genomic
abnormalities is essential. Single nucleotide polymorphism (SNP) arrays represent a cost-effective and
widely accessible method for detecting copy number variations (CNVs) with genome-wide resolution,
making them particularly suitable for quality control (QC) in cell culture systems.
Despite the established utility of SNP arrays for CNV detection, there remains a lack of comprehensive,
user-friendly software solutions that support end-to-end analysis tailored to hPSC line quality assessment.
Existing tools are either limited to discrete analysis steps requiring specialized bioinformatics expertise or
are proprietary solutions that do not adequately address the specific needs of cell line monitoring.
To bridge this gap, we developed an accessible and integrated analysis pipeline for SNP array-based QC of
hPSC lines. The pipeline facilitates all stages of analysis—from raw data processing to the generation of
interpretable reports—and includes specialized features such as sample-to-reference comparison, a CNV
scoring system according to CNV biological impact, single nucleotide variation (SNV) evaluation and
identity verification via SNP genotyping profiles, all tailored to hPSC. We benchmarked the pipeline against
established methodologies and implemented strategies to enhance CNV detection reliability through
expert-guided improvement process
Anchor-based evaluation of digital motor biomarkers from a 2-year observation in 100 patients with multiple sclerosis
Get PDFBACKGROUND: Description of disease progression in MS lack sensitive clinical outcomes. Digital motor outcomes (DMO) offer potential but require thorough validation. OBJECTIVE: This 2-year observational study explores the sensitivity of 26 DMO derived from a task-based assessment protocol via RGB-D camera. METHODS: One-hundred people with MS (pwMS) were enrolled, 96 completed follow-up. Expanded Disability Status Scale (EDSS) and 12-Item MS Walking Scale (MSWS-12) served as anchors for sensitivity by classifying progression, improvement or stable at 2 years, irrespective of intercurrent relapses. Primary analysis applied linear mixed modeling. Distribution-based thresholds (MDC) were calculated from stable subgroups. RESULTS: Six DMO showed a significant increase over time in relation to stand-up/sit-movement (β = 0.01; β = 0.02), stepping asymmetry (β = 0.02; β = 0.02), trunk deflection while walking (β = 0.02) and trunk sway in closed-eyes stance (β = 0.02) (95% CI 0.001-0.038; all p < 0.05). EDSS (n = 22) and MSWS-12 (n = 11) progression groups were distinct. Time effects differed by anchor. For the EDSS progression group, the change in step width and sway velocity in closed-feet/open-eyes stance exceeded measurement error. CONCLUSIONS: Our findings yield a well-applicable set of DMO that may support definitions of disability accumulation in (early) pwMS. Establishing patient relevance remains challenging due to expectedly low clinical progression rates. The distinct patterns captured by EDSS and MSWS-12 definitions underline the need for multiple anchors when validating new biomarkers
Extrachromosomal DNA associates with poor survival across a broad spectrum of childhood solid tumors
Get PDFCircular extrachromosomal DNA (ecDNA) is a common form of oncogene amplification in aggressive cancers. The frequency and diversity of ecDNA has been catalogued in adult and some childhood cancers; however, its role in most pediatric cancers is not well-understood. To address this gap, we accessed large pediatric cancer genomics data repositories and identified ecDNA from whole genome sequencing data using cloud computing. This retrospective cohort comprises 3,631 solid tumor biopsies from 2,968 patients covering all major childhood solid tumor types. Aggressive tumor types had particularly high incidences of ecDNA. Pediatric patients whose tumors harbored extrachromosomal DNA had significantly poorer five-year overall survival than children whose tumors contained only chromosomal amplifications. We catalogue known and potentially novel oncogenes recurrently amplified on ecDNA and show that ecDNA often evolves during disease progression. These results highlight patient populations that could potentially benefit from future ecDNA-directed therapies. To facilitate discovery, we developed an interactive catalogue of ecDNA in childhood cancer at https://ccdi-ecdna.org/